This invention relates to the field of molecular recognition of small ligands. More particularly, the invention relates to compositions useful for the purification of enantiomers of amino acid derivatives and for the purification of certain compounds able to form hydrogen bonds, methods for preparing these compositions, and methods for using them.
Standard approaches to the optical resolution and purification of organic and biological molecules include crystallization, distillation, extraction, and chromatography (Eliel, Stereochemistry of Carbon Compounds, New York: McGraw-Hill, 1962). Each methodology is based on a physical or chemical interaction of a molecule with an element of its environment, and may involve molecular sizing, electrostatics, hydrophobicity, sterics, or polarity. The efficiency of purification increases as the differences in interaction energy for all the species present in the mixture increase. The relevant interactions for crystallization are crystal lattice forces and solvation of the molecule; for distillation, the interaction is a liquid-gas phase transition; while for extraction and chromatography, the interaction is exchange between non-miscible phases. Common to all these classic methods is the limitation that as molecular structures become increasingly similar, the energy differentials for the relevant interaction diminish to the extent that high resolution is no longer feasible. A general approach to purification necessitates an enhanced capability for transcending this natural tendency toward shrinking energy differences. The ability to purify very similar or chiral molecules is of economic and practical importance to the developing fields of biotechnology, and should greatly accelerate the development of new pharmaceuticals and bioactive and other useful compounds.
The ability to distinguish similar molecules is an important goal of research in the field of molecular recognition. Early efforts to bind molecules selectively involved naturally occurring host molecules, such as clathrates, cholic acid, and cyclodextrins (Diederich, Anew. Chem. Int. Ed. End., 27, 362 (1988); Breslow, Science (Washington, D.C.), 218, 532 (1982)). The first example of a synthetic system specifically designed to undergo inclusion complexation was a cyclophane (Stetter & Roos, Chem. Ber., 88, 1390 (1955)). Synthetic crown ethers and cyclic polyamines were designed to complex metal ions selectively by adjusting ring size and number of heteroatoms (Pederson, Angew. Chem. Int. Ed. Eng,, 16, 16 (1972)). Macrobicyclic compounds have been prepared which show selectivity for trihydrobenzenes with certain substitution patterns (Ebmeyer and Vogtle, Angew. Chem. Int. Ed. Engl., 28, 79 (1989)).
The use of chiral components in constructing host compounds has led to the development of molecules which are, in principle, capable of diasteroselective complexation with chiral guests. While several systems have exhibited some diastereoselectivity, numerous attempts to produce chiral hosts have not produced any known compounds of practical utility prior to the present invention. The earliest preparations of chiral crown amino ethers were applied to cation complexation, and not to chiral discrimination by diastereoselective complexation (Wudl & Gaeta, J. Chem. Soc., Chem. Commun., 107 (1972)). Chiral hosts based on biphenylmacrocycles have shown promise (Kyba, et al., J. Amer. Chem. Soc., 100, 4555 (1978)). A recent example intended to distinguish enantiomers of amino acids and arylpropionic acids however appears from binding studies not to function as a host for nonpolar molecules (Rubin, et al., J. Org. Chem., 51, 3270 (1986)).
High enantioselectivity has thus largely eluded prior workers in the field. A bilaterally symmetric host containing two diiodotyrosine moieties was one of the first to exhibit a measurable difference in binding energy with mirror image guest molecules (Sanderson, et al., J. Amer. Chem. Soc., 111, 8314 (1989)); free energy differences ranged from -0.15 to 0.48 kcal/mole, with binding site saturations up to 67%. More recently, a related chiral host was made with pyridyl moieties replacing benzene rings in the macrocycle, which showed free energy differences up to about 1 kcal/mole and a range of binding saturations of approximately 40-80% (Liu, et al., J. Org. Chem., 55, 5184 (1990)). Chiral hosts in which the enantioselection energies exceed 1 kcal/mole have been virtually nonexistant prior to the present invention.
Progress toward a completely chemoselective or enantioselective host has been limited, proceeding roughly in parallel with growing understanding of intermolecular interactions controlling binding affinity in natural receptors like enzymes and hormone receptors. The present invention provides a composition of matter which possesses enzyme-like enantioselectivity which is sufficiently high to offer practical utility in optical resolution and chemical purification of organic compounds.